JPH0717665B2 - Unsaturated amino acid and method for producing the same - Google Patents

Abstract

Phosphorus-contg. unsaturated amino acids of formula (I) and their salts are new: R1 = hydroxy or etherified hydroxy; R2 = H, alkyl, hydroxy or etherified hydroxy; R3 = H, alkyl, haloalkyl, hydroxyalkyl, lower alkoxyalkyl, arylalkyl, lower alkenyl, halogen or aryl; R4 = H, alkyl or arl; R5 = H or alkyl; R6 = carboxy or esterified or amidated carboxy; R7 0 amino opt. substd. by alkyl or aryl; A = opt. alkyl-substd. 1-3C alpha, omega-alkylene or a direct bond; B = methyleue or direct bond; provided that A and B are both direct bonds. Specifically claimed are 9 cpds. including E-2-amino-5- phosphono-3-pentenoic acid, E-2-amino-4-methyl-5-phosphono -3-pentenoic acid, and E-2-amino-4-methyl -5-phosphono-3-pentenoic acid ethyl ester.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to novel unsaturated amino acids or salts thereof, and methods for producing these novel substances.

[Outline of Invention]

The compound of the present invention has the following general formula (I): 2-amino-ω-phosphono-alk-3, wherein R ³ is hydrogen or lower alkyl and R ⁶ is carboxyl esterified with carboxyl or lower alkyl.
-Enoic acid compounds and pharmaceutically acceptable salts.

[Specific explanation]

The compounds of general formula (I) contain one chiral center and are in the form of enantiomers or enantiomeric mixtures such as racemates, and if they contain more than one chiral center they are also diastereomeric. It is also in the form of a stereoisomer or a mixture of diastereoisomers.

The carbon-carbon double bonds of the compounds according to the invention are in the trans-configuration, ie the compounds of general formula (I) are of the E-series.

Salts of the compounds according to the invention are pharmaceutically acceptable non-toxic salts of compounds of general formula (I). Such salts are formed, for example, from the carboxy groups present in the compounds of general formula (I), especially metal salts such as alkali metal and alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or ammonia or Suitable organic amines such as lower alkylamines such as methylamine, diethylamine, triethylamine, such as 2-hydroxyethylamine, bis- (2-hydroxyethyl)
-Amine, tris- (hydroxymethyl) -methylamine or tris- (2-hydroxyethyl) -amine,
Basic aliphatic esters of carvone such as 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkyleneamines such as 1-ethylpiperidine, lower alkylenediamines such as ethylenediamine, cycloalkylamines such as dicyclohexylamine, or benzylamines such as It is an ammonium salt with N, N-dibenzylethylenediamine, benzyltrimethylammonium hydroxide, dibenzylamine or N-benzyl-β-phenylethylamine. The compounds of general formula (I) having primary or secondary amino groups also form acid addition salts and are preferably pharmaceutically acceptable, for example hydrohalic acids such as hydrochloric acid or bromic acid, sulfuric acid, nitric acid or phosphoric acid. Inorganic acid, or a suitable organic carboxylic acid or sulfonic acid, such as acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, fumaric acid, maleic acid, tartaric acid, oxalic acid, citric acid, pyruvic acid, benzoic acid, mandelic acid, It forms a salt with malic acid, ascorbic acid, pamoic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid or naphthalenesulfonic acid.

It is also possible to use pharmaceutically unsuitable salts for isolation or purification. Only pharmaceutically acceptable non-toxic salts are used therapeutically, and these are therefore preferred.

The general terms used above have the following meanings unless otherwise defined hereafter.

The term "lower" indicates that the correspondingly defined group or compound contains up to 8 and preferably up to 4 carbon atoms.

Lower alkali is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or ter.
t.-Butyl, preferably methyl.

Lower alkoxy in lower alkyl ester is especially methoxy, ethoxy, n-propoxy, isopropoxy, n-
Represents butoxy, isobutoxy or tert.-butoxy.

The compounds of the present invention have valuable pharmaceutical properties. For example, they are active and selective antagonists of N-methyl-D-aspartic acid (NMDA) -sensitive excitatory amino acid receptors in mammals. They are therefore NMDA-
It is suitable for the treatment of diseases that respond to blockade of sensitive receptors, such as cerebral ischemia, muscle spasm (spasticity), spasm (tencan), anxiety or mania.

These beneficial effects are shown in in vitro or in vivo tests. For these, preferably mammals such as mouse, rat or monkey, or tissues or enzyme preparations of such mammals are preferably used. These compounds are administered enterally or parenterally, preferably orally, or subcutaneously, intravenously or intraperitoneally,
For example, it is administered in the form of a gelatin capsule or an aqueous suspension or solution. The dose used in vivo is 0.1
The range is from to 600 mg / kg, preferably from 1 to 300 mg / kg. In vitro, these compounds are used in the form of aqueous solutions, with concentrations ranging from 10 ^-4 to 10 ^-8 molar.

The inhibitory effect on the NMDA-sensitive excitatory amino acid receptor was observed in vitro by G. Fagg and A. Matus [G. Fagg and A. Ma.
tus, Proc, Nat, Acad.Sci. , USA, how NMDA- sensitive receptors ^L-3 to H according 81,678-80 (1984)]
-It is determined by measuring whether the binding of glutamic acid is suppressed. In vivo, the inhibitory effect on the NMDA-sensitive excitatory amino acid receptor is NM in mice.
Shown by inhibition of DA-induced convulsions.

The antispasmodic properties of the compounds according to the invention are also their DBA /
2 also demonstrated by their effectiveness in preventing auditory-induced seizures in mice [Chapman et al. Arzneimittel-Forsch. 34,1261,
1984].

This anti-convulsive property is further demonstrated by the effectiveness of the compounds according to the invention as electroshock antagonists in mice or rats.

The compounds of the present invention show their anxiolytic activity in their Cook / Davidson, Psychopharmacologia 15,159.
-168 (1968)], given their remarkable effectiveness in the conflict model.

The remarkable effectiveness of the compounds of general formula (I) depends to a surprisingly high extent on the configuration at the double bond.
For example, Agric. Biol. Chem. 41, 573-579 (1979), BK
The racemic form of D-2-amino-5-phosphono-3-cis-pentenoic acid known from BK Park et al. Is, for example, in its ability to bind to NMDA-sensitive receptors 2-amino-according to the invention. It was found to be much inferior to 5-phosphono-3-trans-pentenoic acid (these compounds are referred to as "E-series" compounds in the examples).

Of the compounds of general formula I, those in which R ³ represents alkyl are preferred.

The compound of the present invention is produced by a method known per se,
For example, manufactured as follows: The following formula (II): Wherein R ³ is hydrogen or lower alkyl, X is reactive esterified hydroxy, Z ⁶ is carboxy or protected carboxy, and Z ⁷ is amino or protected amino. The compound represented is represented by the following formula (III): Where Z ¹ and Z ² are hydroxy or protected hydroxy and R is an etherifying group, and the protected functional group in the compound resulting from the previous step is If present, it is liberated and optionally the resulting compound of formula (I) is converted to a lower alkyl ester of formula (I) and / or optionally the resulting compound of formula (I) is of the formula (I) The salt or the resulting salt is converted to another salt or to the free compound, and / or optionally the resulting compound of formula (I) or a mixture of stereoisomeric forms of the salt is separated into optical isomers.

In the above process, protected hydroxy and protected amino have the meanings, for example, for said protected hydroxy and acyl-substituted amino, where protected hydroxy especially represents lower alkoxy and protected amino is Particularly, it represents lower alkanoylamino. Another preferred example of protected hydroxy is a tri-lower alkylsilyl, for example a trisubstituted silyl such as trimethylsilyl or tert.-butyldimethylsilyl.

Furthermore, the protected amino is substituted by a 2-halo-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2-tri-lower alkylsilylethoxycarbonyl, for example substituted by 2- (tris-substituted silyl) -ethoxycarbonyl such as 2-trimethylsilylethoxycarbonyl or 2- (di-n-butyl-methyl-silyl) -ethoxycarbonyl. Alternatively, 2-triphenylsilylethoxycarbonyl and the like 2-
It may be amino substituted with lower alkoxycarbonyl, such as amino substituted with triallyl-silylethoxycarbonyl, or etherified mercaptoamino or silylamino, or in the form of an enamino, nitro or azido group. You may

Etherified mercaptoamino groups are especially methyl, tert.
A lower alkyl such as butyl, a lower alkoxy such as methoxy, a halogen such as chlorine or bromine, and / or a phenylthioamino group optionally substituted with nitro, or a pyridylamino group. Corresponding groups are for example 2- or 4-nitrophenylthioamino or 2-pyridylthioamino.

Silylamino groups are especially organic silylamino groups. In such groups, the silicon atom preferably contains as substituents lower alkyl such as methyl, ethyl, n-butyl or tert.-butyl, and aryl such as phenyl. Suitable silyl groups are especially tri-lower alkylsilyl, especially trimethylsilyl or dimethyl-tert.-butylsilyl.

The enamino group contains an electron-withdrawing substituent such as a carbonyl group at the double bond at the 2-position. A protecting group of this kind is, for example, a 1-acyl-lower alk-1-en-2-yl group, in which the acyl is for example a lower alkanecarboxylic acid, such as acetic acid, optionally methyl or te
benzoic acid substituted by lower alkyl such as rt.-butyl, lower alkoxy such as methoxy, halogen such as chlorine and / or nitro, or especially carbonic acid lower alkyl half ester such as methyl half ester or ethyl half ester The corresponding group of esters and lower-alk-1-ene is especially 1-propene. Corresponding protecting groups are especially 1-lower alkanoyl-prop-1-
En-2-yl, for example 1-acetyl-prop-1-en-2-yl, or 1-lower alkoxycarbonyl-
Prop-1-en-2-yl, for example 1-ethoxycarbonyl-prop-1-en-2-yl.

The protected carboxy is usually protected in the esterified form and the ester group is reductive (e.g. hydrogenolytically) or solvolytically (e.g. acidolytic or acidic-
It can be removed under hydrolysis conditions such as hydrolysis, basic-hydrolysis or neutral-hydrolysis. The protected carboxyl group can be further easily converted into an esterified carboxy that can be cleaved under physiological conditions, or a different functional modified carboxy group such as a different esterified carboxyl group. It can be an esterified carboxy group which can be

Such esterified carboxy groups contain as esterified groups a lower alkyl group branched in the 1-position or appropriately substituted in the 1- or 2-position.
Preferred carboxy groups in the esterified form are especially lower alkoxycarbonyl, such as methoxy-carbonyl, ethoxycarbonyl, 2-propoxycarbonyl or tert.-butoxycarbonyl, and having 1 to 3 aryl groups or 1 monocyclic heteroaryl. (Hetero) arylmethoxycarbonyl having a group, these optionally being for example tert.-lower alkyl, for example tert.-
Lower alkyl such as butyl, halogen such as chlorine and /
Or it is mono- or poly-substituted by nitro.
Specific examples of such groups include, for example, benzyloxycarbonyl which may be substituted as described above, for example 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl which may be substituted as described above, for example diphenyl. Methoxycarbonyl, or triphenylmethoxycarbonyl, or picolyloxycarbonyl optionally substituted as described above, for example 4-picolyloxycarbonyl, or furfuroxycarbonyl such as 2-furfuryloxycarbonyl.

The protected hydrogen Z ¹ is protected by methods known per se, for example as described in EP-A-0 009 348. The corresponding protecting group is preferably of the general formula —C (C _1-4
-Alkyl) (ORa) ORb, preferably the general formula -CH (OR
a) ORb (wherein Ra and Rb each represent C _1-4 -alkyl)
Is a group represented by. Particularly suitable is --CH (OC ₂ H
₅ ) _Two units.

Reactive esterified hydroxy groups such as X are hydroxy groups esterified with strong organic acids, such as aliphatic or aromatic sulfonic acids (eg lower alkane sulfonic acids,
Methanesulfonic acid, trifluoromethanesulfonic acid, especially benzenesulfonic acid, p-toluenesulfonic acid, p-bromobenzenesulfonic acid, and p-nitrobenzenesulfonic acid) or a strong inorganic acid such as sulfuric acid, or hydrochloric acid, or most preferably It is a hydroxy group esterified with hydrohalic acid such as hydroiodic acid or hydrobromic acid.

In this method, the etherifying group R is, for example, phenyl-lower alkyl, trisubstituted silyl, such as tri-lower alkylsilyl, or preferably alkyl. The reaction is carried out in a manner known per se, in particular under the known conditions of the Michaelis-Arbuzov reaction.

According to one variant of this method, for example, the general formula (III)
The reaction with a trialkyl phosphite such as triethyl phosphite, in particular with a compound of the general formula (II) in which A represents a bond, is carried out by a suitable method, for example a halide of a metal of group VIII, preferably nickel halide, palladium or It can be catalyzed by platinum, especially nickel chloride.

In this process, if some of Z ¹ , Z ² , Z ⁶ and Z ⁷ represent protecting groups, these are advantageously chosen such that they are liberated in a single step. The conditions under which these protecting groups are liberated are preferably those with acid hydrolysis, such as hydrohalic acid such as hydrochloric acid, preferably with heating.

The work-up is carried out in a manner known per se, with two purification operations being particularly advantageous. The crude product is converted to an easily volatile derivative, for example, by silylation and directly obtained by distillation, followed by desilylation, or the crude product is acidified by adding a reagent that reacts with an excess acid such as hydrohalic acid. May be removed. For example, the compounds to which the corresponding acids are added, such as lower alkylene oxides (epoxides), such as propylene oxide, come into consideration.

In this method, R ³ is as defined for general formula (I), Z ¹ represents a protected hydroxy group, Z ² represents protected hydroxy, R represents lower alkyl and Z ⁶ represents It is possible to carry out the reaction with a compound which represents a protected carboxy, Z ⁷ represents a protected amino and X represents a reactive esterified hydroxy, and to remove the protecting group following the reaction in which the compound RX is free. preferable. In this case, preferably R ¹ and Z ² represent lower alkyl, di-lower alkoxy-lower alkyl or lower alkoxy, R represents lower alkyl, Z ⁶ represents lower alkoxycarbonyl and Z ⁷ represents formylamino. And X represents halogen.

The compound represented by the general formula (II) is produced, for example, by reacting an α, ω-unsaturated aldehyde such as acrolein or methacrolein with an α-isocyanoacetic acid derivative such as α-isocyanoacetic acid lower alkyl ester. By a suitable catalytic reaction using a metal oxide or metal halide such as a low-valent metal salt such as zinc chloride, cadmium chloride, silver oxide or preferably copper oxide,
5-Vinyl-2-oxazoline-4-carboxylic acid derivatives, such as esters, can thus be obtained by methods known per se and converted into closed compounds of the general formula (IX): These compounds are then subjected to selective halogenation, such as bromination or chlorination, preferably with cooling and by substitution of the double bond by the method of allylic rearrangement, with the general formula (I
It may be converted to a compound of I).

In order to convert the obtained compound of the general formula (I) into a different compound of the general formula (I), the following conversion may be carried out.

A free carboxylic acid of the general formula (I) or a salt thereof is converted into a corresponding ester by a suitable alcohol or a corresponding derivative thereof, that is, for example, a lower alkyl ester according to a known method, ie, a compound of the general formula (I) Can be converted to

For esterification, the carboxylic acid is directly reacted with a diazoalkane, especially diazomethane, or the corresponding alcohol, a strong acid catalyst (eg hydrohalic acid, sulfuric acid or organic sulfonic acid) and / or a dehydrating agent (eg dicyclohexylcarbodiimide). ) May be allowed to react. Alternatively, the carboxylic acid is converted into a reactive derivative such as a reactive ester or a mixed anhydride using, for example, an acid halide (especially an acid chloride) and the activated intermediate is reacted with the desired alcohol.

The above reactions are preferably inert to the reagents according to standard methods and in the presence or absence of diluents which are their solvents, in the presence of catalysts, condensing agents and other reagents, and / or an inert atmosphere. At low temperature, room temperature or high temperature, preferably at the boiling point of the solvent used, at atmospheric pressure or superatmospheric pressure.

The invention further provides that the intermediate obtained in any stage of the process of the invention is used as a starting material and the remaining steps are carried out, or the process is interrupted in any stage, or the starting material is under reaction conditions. And the reactants used in the form of their salts or optically pure enantiomers. In these reactions the starting materials should be used in particular so as to form the compounds mentioned above as being particularly valuable.

The invention also relates to new starting materials and processes for their preparation.

Depending on the choice of starting materials and methods, these novel compounds are one form of possible optical isomers or mixtures thereof, for example they are antipodes, depending on the number of asymmetric carbon atoms. In the form of a pure optical isomer or a mixture of optical isomers such as a racemate or a mixture of diastereoisomers, and one enantiomer is isolated therefrom if desired.

The resulting mixture of diastereoisomers and the mixture of ceramines are separated into pure isomers, diastereoisomers or racemates, for example by chromatography and / or fractional crystallization, based on the physical-chemical differences between the constituents. You may

The racemate obtained (racemic diastereoisomer) is obtained according to a method known per se, for example with the aid of a microorganism, or by recrystallization from an optically active solvent, or with the racemic acid of the acidic target product. The salt is formed by reaction with an optically active base, and the salt thus obtained is separated into diastereoisomers, for example on the basis of their different solubilities, and then the antipodes are treated with the appropriate reagents. It can be separated into an optical antipode by being released by. The basic racemic product can also be separated into its antipodes, for example by separating its diastereoisomeric salts, for example by fractional crystallization of its d- or 1-tartrate salt. Any racemic intermediate or starting material can be separated as well.

Finally, the compounds according to the invention are obtained either in free form or in the form of their salts. Any resulting base can be converted to the corresponding acid addition salt, preferably using a pharmaceutically acceptable acid or anion exchange formulation, or the resulting salt can be, for example, a strong base such as an alkali metal hydroxide. Alternatively, it can be converted to the corresponding free base using a metal such as carbonate or ammonium hydroxide or a basic salt or a cation exchange preparation. The compounds of general formula (I) can also be converted into the corresponding metal or ammonium salts. These or other salts, such as picrates, can also be used to purify the resulting base. These bases are converted to salts, the salts are separated and the bases are liberated from the salts. In view of the close correlation between the compounds of the free compounds and their salts, when a compound is referred to in this application, this is the correspondence of that compound, if this is possible or appropriate under the given conditions. Also included are salts.

These compounds, including their salts, are obtained in the form of their hydrates, or may contain other solvents used for crystallization.

The pharmaceutical purification according to the present invention includes humans for the treatment or prevention of diseases corresponding to NMDA-receptor blockade such as cerebral ischemia, muscle spasm (spasticity), spasm (tencan), anxiety state or mania state. It is suitable for enteral administration such as oral or rectal administration and parenteral administration to mammals. They comprise an effective amount of a pharmacologically active compound of general formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with one or more pharmaceutically acceptable carriers.

The pharmacologically active compound of the present invention is used for the manufacture of a pharmaceutical composition which is combined with or mixed with an effective amount of itself or an excipient or carrier suitable for enteral or parenteral administration. be able to. Preferred are the active ingredients a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, b) lubricants such as silica, talc, stearic acid, its magnesium or calcium salts and / or Polyethylene glycol or, for tablets, c) binders, such as magnesium aluminum silicate, denpen paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, optionally d) dispersants or disintegrants such as starches. , Agar, alginic acid or its sodium salt, or effervescent mixture and / or e) tablets and gelatin capsules together with absorbents, colorants, flavors and sweeteners. Injectable formulations are preferably aqueous isotonic solutions or dispersions, and suppositories are advantageously prepared from fatty emulsions or suspensions. These compositions are sterilized and / or adjuvant, such as preservatives, safety agents, wetting agents or emulsifiers,
It may contain a solubilizer, salts for controlling the osmotic pressure, and / or a buffer. In addition, they may also contain other therapeutically valuable substances. These formulations are prepared according to the usual mixing, granulating or coating methods and contain about 0.1-100%, preferably 1-50% active ingredient. A unit dose for a mammal weighing about 50 to 70 kg contains about 1 to 500 mg, preferably 10 to 500 mg of active ingredient.

The following examples are illustrative of the invention and are not limiting. Temperatures are in degrees Celsius and all parts are given in parts by weight. Unless otherwise noted, all evaporations are performed under reduced pressure, preferably between about 2 and 13 kilopascals (kPa).

E-2-Amino-4-methyl-5-phosphono-3-pentanoic acid representative of the compounds of the invention (compound of Example 2)
Shows a toxicity of LD ₅₀ = 300 mg / kg upon oral administration to rats, and (D) -E-2-amino-4-methyl-5-phosphono-3-pentanoic acid (compound of Example 8b) It shows a toxicity of LD ₅₀ = 200-1000 mg / kg in oral administration to mice and LD ₅₀ = 100-500 mg / kg in oral administration to mice.

Example 1 8.22 g of E-2-formylamino-5-diethylphosphono-3-pentenoic acid ethyl ester was dissolved in 170 ml of 6N hydrochloric acid and the whole solution was heated under reflux for 22 hours. After concentration in vacuo the oily residue was taken up in a little ethanol and the mixture was evaporated in vacuo again and concentrated. This operation was repeated twice more. The residue obtained was dissolved in 15 ml of ethanol and 20 ml of ethanol / propylene oxide (1: 1) was added dropwise. The brown precipitate obtained was filtered off and purified by ion exchange chromatography (Dowex 50W × 8 / H ₂ O). After concentration and freeze-drying,
E-2-amino-5-phosphono-3-pentenoic acid was obtained as a white amorphous powder. ¹ H-NMR (D ₂ O): 2.39 (dd, 2H, C
(5) -H); 4.27 (d, 1H, C (2) -H); 5.53 (m, 1H, C
(3) -H); 5.87 (m, 1H, C (4) -H). Melting point 191-192 ° after recrystallization from ethanol / water.

The starting material was prepared as follows.

1.6 g of red copper (I) oxide was added to 200 ml of benzene. A solution of 140 g of isocyanoacetic acid ethyl ester and 84 g of freshly distilled acrolein in 200 ml of benzene was added dropwise to this suspension within 10 minutes with vigorous stirring. During this addition, the reaction temperature was maintained at 30-32 ° by cooling with ice. When the addition was complete, the mixture was maintained at 30-32 ° until the exothermic reaction subsided, then the entire mixture was stirred at room temperature for 1 hour. After the excess copper (I) oxide was removed by filtration, the filtrate was concentrated by vacuum evaporation at 30 °. 600 ml of ether were added to the residue, the whole mixture was filtered over Celite and concentrated to dryness by vacuum evaporation. In this way 5
-Vinyl-2-oxazoline-4-carboxylic acid ethyl ester was obtained in the form of a pale yellow oil. Boiling point 100-110 ° (5.
3Pa).

128 g of 5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester were dissolved in 70 ml of tetrahydrofuran and 27.4 g of water and 3.4 g of triethylamine were added. Stir the reaction at 65-70 ° C for 62 hours, allow to cool and then
Take up in 0 ml of dichloromethane. The solution was dried over 200 g magnesium sulphate, filtered and concentrated by vacuum evaporation. Purification of the remaining viscous oil by column chromatography (silica gel; hexane / ethyl acetate 3: 2) gave 2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester in the form of a diastereoisomeric mixture. Melting point 50-51 °.

2.0 g of 2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester in 80 ml of dry tetrahydrofuran were cooled to -78 °. 25 ml of thionyl bromide were slowly added to it so that the reaction temperature did not exceed -75 °. Upon completion of addition, the reaction was warmed to 0 ° within about 3 hours and stirred at that temperature for 2.5 hours. The orange-yellow solution is then poured into 300 ml of cold (5-10 °) saturated aqueous sodium hydrogen carbonate solution,
It was extracted with dichloromethane. The organic extract was dried over magnesium sulfate and concentrated by vacuum evaporation at room temperature. The residual oil was dissolved in 20 ml triethylphosphite,
Heated under reflux (55 °) under vacuum (10 kPa) for 2 hours. Excess triethylphosphite was then distilled off under high vacuum. Purification by column chromatography (silica gel, ethyl acetate / hexane (2: 1), then ethyl acetate) gave E-2-formylamino-5-diethylphosphono-.
3-Pentenoic acid ethyl ester was obtained in the form of a pale yellow oil. ¹ H-NMR (CDCl ₃ ): 2.62 (m, 2H, C (5) -H); 5.19
(M, 1H, C (2) -H); 5.75 (m, 2H, C (3) -H and C
(4) -H).

Example 2 E-2-amino-4-methyl-5-phosphono-3-pentenoic acid was treated in the same manner as in Example 1 with E-2-formylamino-4-methyl-5-diethylphosphono-3-pentenoic acid. Obtained by hydrolysis of the ethyl ester. ¹ H-NMR (D
_{2 O): 1.73 (s,} 3H, CH 3); 4.55 (s, 1H, C (2) -H).

The starting material was prepared as follows.

5- (2-Propenyl) -2-oxazoline-4-carboxylic acid ethyl ester was obtained as a colorless oil by reaction of isocyanoacetic acid ethyl ester with methacrolein as in Example 1 and after subsequent fractional distillation. . Boiling point 11
0-130 ° (5.3Pa).

2-formylamino-3-hydroxy-4-methyl-4
5- (2-propenyl) -2-oxazoline-pentenoic acid ethyl ester, melting point 67 °, as in Example 1.
Obtained by hydrolysis of 4-carboxylic acid ethyl ester.

2-formylamino-3-hydroxy-4-methyl-4
-E-2-formylamino-4-by reacting pentenoic acid ethyl ester with thionyl bromide and subsequently treating with triethyl phosphite as in Example 1.
Methyl-5-diethylphosphono-3-pentenoic acid ethyl ester was obtained in the form of a light yellow color.

Example 3 a) 2.0 g of E-2-amino-5-phosphono-3-pentenoic acid are placed in 50 ml of ethanol and the whole mixture is 21/2 at 50 °.
Saturated with hydrogen chloride gas for hours. After concentration, the residue was dissolved in 18 ml of ethanol, 18 ml of propylene oxide was added, and the precipitate was filtered off. Recrystallization from water / ethanol 1: 3 gave 2-amino-5-phosphono-3-pentenoic acid ethyl ester. Melting point 167-168 °.

b) 2.0 g of E-2-amino-5-phosphono-3-pentenoic acid were suspended in 40 ml of n-butanol and the suspension was saturated with hydrogen chloride gas at 40 ° for 3 hours. 30 ml of residue after concentration
Of n-butanol, 15 ml of propylene oxide was added, and the precipitate was filtered off. Recrystallization from water / acetone 1: 1 gave E-2-amino-5-phosphono-3-pentenoic acid butyl ester. Melting point 160-161 °.

c) 1.5 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of n-propanol and the suspension is adjusted to 50
It was saturated with hydrogen chloride gas at 2 ° for 21/2 hours. The residue after concentration
Dissolved in 15 ml of n-propanol, added 15 ml of propylene oxide and filtered off the precipitate. Water / acetone 1: 3
Recrystallized from E-2-amino-5-phosphono-3-
Obtained pentenoic acid propyl ester. Melting point 161-162 °.

d) 1.5 g of 2-amino-5-phosphono-3-pentenoic acid was suspended in 30 ml of n-pentanol and the suspension was saturated with hydrogen chloride gas at 50 ° for 3 hours. After concentration, the residue was dissolved in 15 ml of n-pentanol, 15 ml of propylene oxide was added, and the residue was filtered off. Recrystallization from water / acetone 1: 1 gave E-2-amino-5-phosphono-3-pentenoic acid pentyl ester. Melting point 160-161 °.

e) 1.5 g of E-2-amino-5-phosphono-3-pentenoic acid were suspended in 30 ml of isobutanol and the suspension was saturated with hydrogen chloride gas at 70 ° for 31/2 hours. After concentration, remove the residue by 10
It was dissolved in ml isobutanol, 10 ml propylene oxide was added and the precipitate was filtered off. Recrystallization from water / acetone 1: 1 gave E-2-amino-5-phosphono-3-pentenoic acid isobutyl ester. Melting point 163-164 °.

f) 1.5 g of E-2-amino-5-phosphono-3-pentenoic acid was suspended in 30 ml of sec-butanol,
It was saturated with hydrogen chloride at 5 ° for 4 hours. 10 ml of residue after concentration
Dissolved in 2-butanol, 10 ml of propylene oxide was added, and the precipitate was filtered off. Recrystallization from water / acetone 1: 1 gave E-2-amino-5-phosphono-3-pentenoic acid sec, -butyl ester. Melting point 169-170 °.

Example 4 Preparation of 1000 capsules containing 10 mg each of the active substance of Example 6 having the following composition: E-2-amino-5-phosphono-3-pentenoic acid 10.0 g lactose 207.0 g modified starch 80.0 g magnesium stearate 3.0 g Method: All powdered components were sieved using a sieve with a 0.6 mm mesh width. The active ingredient was then introduced into a suitable mixer and mixed first with magnesium stearate and then with lactose and starch until homogeneous.
No. 2 gelatin capsules were filled with 300 mg each of this mixture using a capsule-filling machine.

Capsules each containing 10-200 mg of one of the other disclosed compounds listed in the examples were similarly prepared.

Example 5 Preparation of 10,000 tablets each containing 10 mg of the active substance of Example 6 having the following composition: E-2-Amino-5-phosphono-3-pentenoic acid 100.00
g Lactose 2,535.00 g Corn starch 125.00 g Polyethylene glycol 6000 150.00 g Magnesium stearate 40.00 g Purified water qs Method: All powdered constituents were sieved using a sieve with a mesh width of 0.6 mm. The active ingredient was then mixed with lactose, magnesium stearate and half starch in a suitable mixer. The other half starch is 65 ml
Of water and the suspension was added to a boiling solution of polyethylene glycol in 260 ml of water. The resulting paste was added to the powder and the whole mixture was granulated with additional water as needed. The granules were dried overnight at 35 °, passed through a sieve with a 1.2 mm mesh width and pressed to form tablets with fracture channels.

Tablets each containing 10-200 mg of one of the other disclosed compounds listed in the Examples were similarly prepared.

Example 6 E-2-Amino-4-methyl-5-phosphono-3-pentenoic acid was prepared in the same manner as in Example 1 except that E-2-formylamino-4-methyl-5-dimethyl-phosphono-3-pentenoic acid was used. Obtained by hydrolyzing the ethyl ester.
See Example 2 for ¹ H-NMR. In the preliminary fraction, E-2-amino-4-methyl-5-methylphosphono-
3-Pentenoic acid, melting point 149-150 ° was obtained as a by-product.

The starting material was prepared as follows.

2-formylamino-3-hydroxy-4-methyl-4
Ethyl E-2-formylamino-4-methyl-5-dimethylphosphono-3-pentenoate by reacting ethyl pentenoate with thionyl bromide and subsequent treatment with trimethylphosphite as in Example 1. The ester was obtained in the form of a pale yellow oil.

Example 7 a) 2.0 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid are placed in 50 ml of ethanol and the whole mixture is saturated with hydrogen chloride gas at 50 ° for 21/2 hours. It was After concentration, the residue was dissolved in 20 ml of ethanol, 20 ml of propylene oxide was added, and the precipitate was filtered off. Recrystallization from water / ethanol (1: 3) gave E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester.

Melting point 193-194 °.

Similarly, the following ester was obtained: b) E-2-amino-4-methyl-5-phosphono-3-
Pentenic acid methyl ester, melting point 193-194 ° [water / acetone (9: 1)]; c) E-2-amino-4-methyl-5-phosphono-3-
Pentenoic acid n-propyl ester, melting point 184-185 °,
(Water); d) E-2-amino-4-methyl-5-phosphono-3-
Pentenoic acid n-butyl ester, melting point 186-187 °, [water / acetone (2: 1)]; e) E-2-amino-4-methyl-5-phosphono-3-
Pentenoic acid isobutyl ester, melting point 181-182 °, [water / acetone (9: 1), f) E-2-amino-4-methyl-5-phosphono-3-
Pentenoic acid n-pentyl ester, melting point 207-208 °; g) E-2-amino-4-methyl-5-phosphono-3-
Pentenic acid n-hexyl ester, melting point 207-208 °.

Example 8 Racemic separation of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid.

A solution of 1.5 ml of phenylacetyl chloride in 25 ml of 1,4-dioxane was added within 20 minutes at 20 ° to 209 mg of E-2-amino-4-methyl-5 in 21 ml of 2N sodium hydroxide solution.
-Phosphono-3-pentenoic acid was added with vigorous stirring and the whole mixture was stirred at room temperature for 4 hours. 250m reaction solution
It was poured into 1 L of water and extracted repeatedly with dichloromethane. The aqueous phase was concentrated in vacuo to 20 ml at 40 °, prepurified by ion exchange chromatography (DOWEX 50W × 8 / water / 1,4-dioxane 3: 1) and concentrated in vacuo at 40 °. The obtained E-2-
Phenylacetylamino-4-methyl-5-phosphono-
3-Pentenoic acid was adjusted to pH 7.5 with 2N sodium hydroxide solution in 150 ml of water and combined with 250 mg of EUPERGIT-ACYLASE.
The mixture was stirred at 7 ° for 16 hours. After vacuum filtration at 40 °, 10 ml of the mixture
Ion exchange chromatography (DOWEX50W × 8 /
(D) -E-2-phenyl-acetylamino-4-methyl-5-phosphono-3-pentenoic acid and (L) -E-2-amino-4-methyl-5-phosphono-
Separated into 3-pentenoic acid.

a) The aqueous phase of (L) -E-2-amino-4-methyl-5-phosphono-3-pentenoic acid was concentrated in vacuo and the residue was purified by recrystallization from water. Melting point 196 °, [α] ²⁰ _D ▼ = + 97.1 ± 19 ° ( c = 0.5; water).

b) The aqueous phase of (D) -E-2-phenylacetylamino-4-methyl-5-phosphono-3-pentenoic acid was concentrated in vacuo and the residue was stirred with 25 ml of 4.35N hydrochloric acid at 85 ° for 3.5 hours and repeated. It was extracted with dichloromethane. Vacuum concentrate the aqueous phase,
The residue is purified by ion exchange chromatography to (D) -E-2-amino-4-methyl-5-phosphono-
3-pentenoic acid was obtained. Melting point 194 °, [α] ▲ ²⁰ _D ▼ ＝-
96.7 ± 1.2 ° ( c = 0.8; water).

Example 9 E-2-formylamino-4-ethyl-5-dimethylphosphono-3-pentenoic acid ethyl ester at 80 ° C under nitrogen.
Hydrolyzed with 4.35N hydrochloric acid at E-2-amino-4
-Ethyl-5-phosphono-3-pentenoic acid was obtained. Melting point is 176 ° (H ₂ O).

The starting material was prepared as follows.

2-Methyl-butyraldehyde was reacted with ethyl isocyanoacetate in the same manner as in Example 1 to obtain 5- (buten-2-yl) -2-oxazoline-4-carboxylic acid ethyl ester. 100 ml ethanol / water (1: 1)
16 g of 5- (buten-2-yl) -2-oxazoline-4-carboxylic acid ethyl ester in it was boiled under reflux for 15 hours. The whole mixture was concentrated by vacuum evaporation and the residue was
It is taken up in 200 ml of dichloromethane, dried over sodium sulphate, filtered and the filtrate is concentrated by evaporation to give 2-formylamino-
3-Hydroxy-4-ethyl-4-pentenoic acid ethyl ester was obtained.

2-formylamino-3-hydroxy-4-ethyl-4
-Pentenoic acid ethyl ester was reacted with thionyl bromide as in Example 1 and subsequently treated with trimethylphosphite to give E-2-formylamino-4-ethyl-5-dimethylphosphono-3-pentenoic acid ethyl ester. Got

Example 10 E-2-Formylamino-4-propyl-5-dimethylphosphono-3-pentenoic acid ethyl ester was hydrolyzed in the same manner as in Example 9 to give E-2-amino-4-propyl-5-. Phosphono-3-pentenoic acid was obtained. Melting point 193 ° (H
₂ O).

The starting material was prepared as follows.

2-Methylene-pentanal was reacted with isocyanoacetic acid ethyl ester as in Example 1 to give 5- (penten-2-yl) -2-oxazoline-4-carboxylic acid ethyl ester. This 5- (penten-2-yl)-
2-Oxazoline-4-carboxylic acid ethyl ester was hydrolyzed in the same manner as in Example 9 to give 2-formylamino-
3-Hydroxy-4-propyl-4-pentenoic acid ethyl ester was obtained. This 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester was reacted with thionyl bromide as in Example 1 and subsequently treated with trimethylphosphite to give E-2-formylamino-4. -Propyl-5-dimethylphosphono-3-pentenoic acid ethyl ester was obtained.

Example 11 E-2-formylamino-4-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester was hydrolyzed in the same manner as in Example 9 to give E-2-amino-4-butyl-5.
-Phosphono-3-pentenoic acid was obtained. Melting point 180 ° -187 ° (H ₂ O).

The starting material was prepared as follows.

2-Methylene-hexanal was reacted with isocyanoacetic acid ethyl ester in the same manner as in Example 1 to give 5- (hexane-2-yl) -2-oxazoline-4-carboxylic acid ethyl ester, which was designated as Example 9 Similarly hydrolyzed to 2-formylamino-3-hydroxy-4-butyl-
4-pentenoic acid ethyl ester. E-2-Formylamino-4 was prepared by reacting 2-formylamino-3-hydroxy-4-butyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethylphosphite as in Example 1. -Butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester was obtained.

Example 12 E-2-Formylamino-4-isopropyl-5-dimethylphosphono-3-pentenoic acid ethyl ester was hydrolyzed in the same manner as in Example 9 to obtain E-2-amino-4-isopropyl-5-. Phosphono-3-pentenoic acid was obtained. Melting point
201 ° (H ₂ O).

The starting material was prepared as follows.

React 3-methyl-2-methylene-butanol with ethyl isocyanoacetate as in Example 1 to give 5
-(3-Methyl-buten-2-yl) -2-oxazoline-4-carboxylic acid ethyl ester was obtained, which was hydrolyzed in the same manner as in Example 9 to give 2-formylamino-3-hydroxy-4-isopropyl. -4-Pentenoic acid ethyl ester. Subsequently, it was treated with thionyl bromide and reacted with trimethylphosphite in the same manner as in Example 1 to obtain E-2-formylamino-4-isopropyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.

Example 13 3.9 g of E-2-formylamino-4-tert.-butyl-
5-Dimethylphosphono-3-pentenoic acid ethyl ester was hydrolyzed as in Example 9. 1.8g by decomposition by ion exchange chromatography (Dowex W50, H ₂ O)
Of E-2-amino-4-tert.-butyl-5-phosphono-3-pentenoic acid and 0.075 g of Z-2-amino-4-te.
rt.-Butyl-5-phosphono-3-pentenoic acid was obtained.

E-isomer: melting point 252-253 ° (H ₂ O); ¹ H-NMR (D ₂ O): 0.95 (s, 9H, (CH ₃ ) C); 2.65 (m, 2H, C
H ₂ ); About 4.7 (d, 1H, C (2) -H); 5.33 (m, 1H, C (3)
-H).

Z-isomer: ¹ H-NMR (D ₂ O): 1.08 (s, 9H, (CH ₃ ) ₃ C);
_{2.45 (m, 2H, CH 2} ); 4.95 (d, 1H, C (2) -H); 5.20 (m,
1H, C (3) -H).

The starting material was prepared as follows.

In the same manner as in Example 1, 3,3-dimethyl-2-methylene-
Butanol was reacted with isocyanoacetic acid ethyl ester to give 5- (3,3-dimethylbuten-2-yl) -2-oxazoline-4-carboxylic acid ethyl ester, which was hydrolyzed as in Example 9. To 2-formylamino-3-hydroxy-4-tert.-butyl-4-pentenoic acid ethyl ester. Subsequent reaction with thionyl bromide as in Example 1 followed by treatment with trimethylphosphite gave E-2-formylamino-4-tert.-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester. Obtained.

Example 14 The following test results are from G. Fagg and A. Matus, Proc. Nat. Acad. Sc.
It was obtained for a representative compound of the present invention in an L-glutamate binding test according to i.USA, Vol. 81, p6876-6880 (1984).

Compounds of Examples IC ₅₀ (μmol) 1 0.3-0.8 2 0.24 11 0.37 The following test results are from Turski et al., Neuroscience Letters Vo.
Inhibition of NMDA-induced seizures in mice by l.73, p143-147 (1987) was obtained for representative compounds of the invention.

Example compound mg / kg (intraperitoneal) 1 8 2 1-5 7a 1-5 7b 1-5 7c 1-5 7d 1-5

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Derek Edward Brandish West Sussex ARL, UK, 13 6 Dieu, Horsham, Smithburn 70 (72) Inventor John Gray Dingwall Switzerland, 4412 Nugrar, St. Panta Leonstraße 16 (72) Inventor Graham Eric Fagg, Switzerland, 4125 Lien, Benderins Gasse 1 (56) References US Pat. No. 4,438,583 (US, A) Chem. Abs. , 86 (25), 184779 r

Claims (8)

[Claims] 1. The following formula (I): Wherein R ₃ is hydrogen or lower alkyl, and R ⁶ is carboxyl or carboxyl esterified by a lower alkyl group, and a 2-amino-ω-phosphono-3-pentenoic acid compound, and A pharmaceutically acceptable salt thereof. 2. (D) -E-2-amino-4-methyl-5
-The compound according to claim 1 which is phosphono-3-pentenoic acid, or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, which is E-2-amino-4-methyl-5-phosphono-3-pentenoic acid, or a pharmaceutically acceptable salt thereof. 4. E-2-Amino-4-methyl-5-phosphono-3-pentenoic acid methyl ester, E-2-amino-
4-Methyl-5-phosphono-3-pentenoic acid ethyl ester, E-2-amino-4-methyl-5-phosphono-3
-Pentenoic acid propyl ester, E-2-amino-4-
Methyl-5-phosphono-3-pentenoic acid n-butyl ester or E-2-amino-4-methyl-5-phosphono-
A 3-pentenoic acid n-hexyl ester.
The compound according to. 5. The following formula (I): Embedded image wherein 2-amino-ω-phosphono-3-pentenoic acid and a pharmaceutically acceptable salt thereof represented by the formula: wherein R ³ is hydrogen or lower alkyl, and R ⁶ is carboxyl. ,
The following formula (II): Wherein R ³ is hydrogen or lower alkyl, X is reactive esterified hydroxy, Z ⁶ is carboxy or protected carboxy, and Z ⁷ is amino or protected amino. The compound represented is represented by the following formula (III): Where Z ¹ and Z ² are hydroxy or protected hydroxy and R is an ether group, and a protected functional group is present in the compound resulting from the previous step. It is liberated and / or optionally the resulting compound of formula (I) is converted to a salt of formula (I) or the resulting salt to another salt or to the free compound and / or optionally of formula (I The process wherein the compound of I) is separated into a mixture of stereoisomeric forms of the salt into optical isomers. 6. Z ¹ and Z ² are lower alkoxy, R is lower alkyl, Z ⁶ is lower alkoxycarbonyl, Z ⁷ is formylamino, and X is halogen. The method described in. 7. The following formula (I): A lower alkyl ester of 2-amino-ω-phosphono-3-pentenoic acid represented by the formula: wherein R ³ is hydrogen or lower alkyl, and R ⁶ is a carboxyl esterified by lower alkyl. And a salt of the following formula (II): Wherein R ³ is hydrogen or lower alkyl, X is reactive esterified hydroxy, Z ⁶ is carboxy or protected carboxy, and Z ⁷ is amino or protected amino. The compound represented is represented by the following formula (III): Where Z ¹ and Z ² are hydroxy or protected hydroxy and R is an etherified group, and the compound resulting from the preceding step has a protected functional group present. Liberating it and converting the resulting compound of formula (I) to a lower alkyl ester of formula (I), and / or optionally converting the resulting compound of formula (I) into a salt of formula (I) or Converting the resulting salt to another salt or to the free compound and / or optionally separating a mixture of the resulting compound of formula (I) or the stereoisomeric forms of the salt into optical isomers. 8. Z ¹ and Z ² are lower alkoxy, R is lower alkyl, Z ⁶ is lower alkoxycarbonyl, Z ⁷ is formylamino, and X is halogen. The method described in.